Small molecules that bind to DNA have been found to profoundly affect fundamental biological processes. The binding can induce mutagenesis and carcinogenesis and antitumor activity. The assumption has been that these DNA-binding molecules interfere with biologically crucial DNA-protein interactions. However, neither the binding mechanism nor the protein interference mechanism is well understood. The objective of this research is to use recently developed DNA isolation and nucleotide-sequencing techniques to gain a better understanding of DNA-drug interactions. Developed from studies on the molecular biology of DNA-protein reactions, these techniques, and the use of restriction endonucleases, have enabled researchers to study the chemistry of several sequence-specific DNA-protein complexes. These complexes make experimental systems that are highly suitable for a study of the effects of small molecules on DNA-protein interactions. Emphasis will be on study of adriamycin and a series of structurally related analogs. Adriamycin is a DNA-intercalating drug that has been widely used in the chemotherapy of cancer. The antitumor activity of this drug relates to DNA binding, so an important aspect of this research will be to determine what features of the molecule are required for the formation of a DNA-drug complex and what features on the molecule can be modified for more effective interference with crucial DNA-protein interactions. The results of these studies should provide a better understanding of the molecular chemistry involved in small-molecule-induced mutagenesis and carcinogenesis and help in the design of more effective antitumor agents that bind to DNA.